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Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis
Rafael Kramann, … , Sushrut S. Waikar, Benjamin D. Humphreys
Rafael Kramann, … , Sushrut S. Waikar, Benjamin D. Humphreys
Published July 20, 2015
Citation Information: J Clin Invest. 2015;125(8):2935-2951. https://doi.org/10.1172/JCI74929.
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Research Article Nephrology Article has an altmetric score of 13

Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis

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Abstract

Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scar-secreting myofibroblasts, ultimately leading to end-stage renal disease. The hedgehog (Hh) pathway transcriptional effectors GLI1 and GLI2 are expressed in myofibroblast progenitors; however, the role of these effectors during fibrogenesis is poorly understood. Here, we demonstrated that GLI2, but not GLI1, drives myofibroblast cell-cycle progression in cultured mesenchymal stem cell–like progenitors. In animals exposed to unilateral ureteral obstruction, Hh pathway suppression by expression of the GLI3 repressor in GLI1+ myofibroblast progenitors limited kidney fibrosis. Myofibroblast-specific deletion of Gli2, but not Gli1, also limited kidney fibrosis, and induction of myofibroblast-specific cell-cycle arrest mediated this inhibition. Pharmacologic targeting of this pathway with darinaparsin, an arsenical in clinical trials, reduced fibrosis through reduction of GLI2 protein levels and subsequent cell-cycle arrest in myofibroblasts. GLI2 overexpression rescued the cell-cycle effect of darinaparsin in vitro. While darinaparsin ameliorated fibrosis in WT and Gli1-KO mice, it was not effective in conditional Gli2-KO mice, supporting GLI2 as a direct darinaparsin target. The GLI inhibitor GANT61 also reduced fibrosis in mice. Finally, GLI1 and GLI2 were upregulated in the kidneys of patients with high-grade fibrosis. Together, these data indicate that GLI inhibition has potential as a therapeutic strategy to limit myofibroblast proliferation in kidney fibrosis.

Authors

Rafael Kramann, Susanne V. Fleig, Rebekka K. Schneider, Steven L. Fabian, Derek P. DiRocco, Omar Maarouf, Janewit Wongboonsin, Yoichiro Ikeda, Dirk Heckl, Steven L. Chang, Helmut G. Rennke, Sushrut S. Waikar, Benjamin D. Humphreys

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Figure 6

Darinaparsin induces myofibroblast-specific cell-cycle arrest, but does not affect the cell cycle of tubular epithelial cells.

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Darinaparsin induces myofibroblast-specific cell-cycle arrest, but does ...
Eight- to ten-week-old WT male mice on a C57BL/6J background were treated with darinaparsin (50 mg/kg, n = 6) or vehicle (n = 6) starting 2 days before UUO surgery and sacrificed on day 3 after surgery. BrDU was injected (100 mg/kg) 3 hours prior to sacrifice. (A) Representative images of kidney sections from UUO and noninjured CLKs costained for Ki67, BrdU, and α-SMA, demonstrating reduced proliferation of interstitial myofibroblasts in UUO kidneys of the darinaparsin-treated group compared with the vehicle-treated group. (Quantification of Ki67+ cells is shown in Supplemental Figure 14.) (B–D) Costaining of sections from noninjured CLKs and UUO kidneys for BrDU (cells in S phase), p-H3 (G2/M phase), and α-SMA allowed quantification of the cell-cycle stages for interstitial myofibroblasts (α-SMA+) and tubular epithelial cells. Darinaparsin treatment resulted in a specific G0/G1 cell-cycle arrest of interstitial myofibroblasts in UUO kidneys (C), whereas the cell-cycle distribution of tubular epithelial cells was not effected (D). (A similar analysis was performed in mice treated from day 2 until day 10 after UUO and is shown in Supplemental Figures 15 and 16). (E and F) Representative Western blots and quantification by IOD of whole UUO kidney lysates for the cyclin-dependent kinase inhibitor p21/CIP1 and p-Rb (Western blots for noninjured CLKs are shown in Supplemental Figure 16). *P < 0.05 by 1-way ANOVA, followed by Bonferroni’s post-hoc test (C); **P < 0.01 by t test (F). Data represent the mean ± SEM. Scale bars: 60 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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